Identification of the components, targets, and magnitude of an effective immune response to HIV are important steps toward the development of effective vaccines or immunotherapies. Although patients with normal CD4+ T cell counts and low levels of plasma virus are a heterogeneous group, a small subgroup of patients with truly non-progressive HIV infection and restriction of virus replication likely hold important clues to the basis of an effective immune response to HIV. For this reason we have focused considerable attention on groups of such patients who are thought to have immune system mediated restriction of virus replication. It now appears clear that a large fraction of patients previously considered long term non-progressors (LTNPs) ultimately show a decline of CD4+ T cell numbers. A small subpopulation (fewer than 0.8% of HIV infected individuals) shows no signs of progression over a 10 year period. We have assembled a unique cohort of such patients with non-progressive disease. Many of these patients have been infected for 20 years in the absence of antiretroviral therapy with no CD4+ T cell decline, plasma virus below 50 copies per milliliter. We have previously shown that these patients are unique in the ability of their CD8+ T cells to restrict HIV replication when engrafted into experimental animals. Cells from these patients are being used to systematically dissect the mechanisms of immune mediated restriction of virus replication. HIV-specific CD8+ T cell responses of these patients were studied by a combination of standard cytotoxic T cell (CTL) assays, flow cytometric assays, and T cell receptor (TCR) repertoire analysis in comparison with patients with progressive disease. HLA typing revealed a dramatic association between the HLA B*5701 class I allele and nonprogressive infection (88% (14 of 16) vs 9.5% (19 of 200) in progressors). The gag-specific CD8+ T cell response in the LTNP group was highly focused on peptides previously shown to be B57 restricted. These findings indicated that within this phenotypically and genotypically distinct cohort, a host immune factor is highly associated with restriction of virus replication and nonprogressive disease. They also strongly suggested a mechanism of virus specific immunity that directly operates through the B5701 molecule. Very high frequencies (0.8-18.0%) of circulating CD8+ T cells were found to be HIV specific. However, high frequencies of HIV specific CD8+ T cells were not limited to LTNP with restriction of plasma virus. Because these patients are not distinquished by the frequencies of HIV-specific T cells, these data suggested other qualitative properties of HIV-specific CD8+ T cells may distinguish the response of LTNP from those of progressors. We have recently observed that LTNP are distinguished by the maintenance of HIV-specific CD8+ T cells with a high proliferative capacity. This proliferation is coupled to or parallels perforin expression. By comparison, the HIV-specific CD8+ T cells of progressors had a limited proliferative capacity, limited ability to upregulate perforin expression, and accumulated in early G1 of the cell cycle. These results indicate that LTNP are differentiated by increased proliferative capacity of HIV-specific CD8+ T cells linked to enhanced effector function. In addition, the relative absence of these functions in progressors may represent a mechanism by which HIV avoids immunological control. Strong HIV specific CD4+ T cell proliferative responses are demonstrable in these LTNP patients. However, they are not demonstrable in the majority of infected patients with progressive disease. It has been presumed that HIV-specific CD4+ T cells are killed upon encountering antigen and maintenance of CD4+ T cell responses in some patients causes the restriction of virus replication. We have recently shown that although proliferative responses were absent in patients with poorly restricted virus replication, HIV-specific CD4+ T cells capable of producing interferon-gamma (IFN-g) were detected. In a separate cohort of 8 patients, interruption of antiretroviral therapy resulted in the rapid and complete abrogation of virus-specific proliferation although HIV-1-specific CD4+ T cells were present in the peripheral blood during viremia. Virus-specific proliferation returned when therapy was resumed and virus replication was controlled. Further, HIV-specific CD4+ T cells of viremic patients could be induced to proliferate in response to HIV antigens when co-stimulation was provided by anti-CD28 antibody in vitro. In an additional cohort of 14 patients undergoing treatment interruptions, strong HIV-specific proliferative responses while on therapy were abrogated during viremia. In 11 of 14 patients, HIV replication was not controlled below 5,000 copies per milliliter of plasma. Thus, HIV-1-specific CD4+ T cells persist but do not proliferate in viremic patients. Taken together, these cross-sectional and longitudinal data suggest the absence of HIV-specific proliferative responses in most untreated patients does not represent a critical defect that permits poorly restricted HIV replication, but rather is a consequence of viremia.